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A J Pappano

Publications and source records attributed to A J Pappano.

At least 37 records · Page 2Linked to original sources
PubMed1993

Carbachol-induced sodium current in guinea pig ventricular myocytes is not regulated by guanine nucleotides.

Muscarinic (M2) receptor occupancy by carbachol induces a tetrodotoxin- and pertussis toxin-resistant Na+ current which underlies its positive inotropic effect in guinea pig ventricular cells. We tested the effect of activating [GTP gamma S, Gpp(NH)p] and inactivating (GDP beta S) guanine nucleotides on this carbachol-induced current because guanine nucleotide binding proteins are reported to transduce the effect of muscarinic agonist. A whole-cell voltage clamp method was used. The carbachol (300 microM)-induced current was not significantly changed at any membrane voltage in the absence and the presence of 10 microM GTP gamma S, 100 microM Gpp(NH)p or 500 microM GDP beta S in the patch pipette (inward current amplitude at -80 mV: -21 +/- 1.5 pA, control; -22 +/- 1.3 pA, GTP gamma S; -20, -16 pA, Gpp(NH)p; -20 +/- 2.3 pA, GDP beta S; n = 31, 11, 2 and 14, respectively). The current amplitude was not affected by prolonged dialysis (120 min) of the cell with Gpp(NH)p and/or by the presence of greater concentrations of guanine nucleotides. On the other hand, 10 microM GTP gamma S directly activated the muscarinic K+ channel current within 60 sec after patch rupture in atrial myocytes; either GTP gamma S or GDP beta S (500 microM) occluded activation of this current by carbachol. When isoproterenol had increased L-type Ca++ current in ventricular myocytes, carbachol-induced inhibition of this current was suppressed when GTP gamma S (10 microM) was present in the pipette solution. Therefore, myocytes were dialyzed with effective concentrations of guanine nucleotides.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Inhibition of sodium pump by l-palmitoylcarnitine in single guinea-pig ventricular myocytes.

We reinvestigated the issue of whether l-palmitoylcarnitine inhibits the Na/K pump in the heart. The effects of l-palmitoylcarnitine or ouabain on the Na/K pump current were studied with the voltage-clamp technique in isolated guinea-pig ventricular myocytes. In myocytes bathed in Tyrode's solution, l-palmitoylcarnitine shifted the current-voltage relation inward at all potentials between -80 and 20 mV. the "U"-shaped difference current seen in l-palmitoylcarnitine was maximal at -30 mV and declined at potentials more positive and negative than this. Under conditions that minimized time-dependent currents, ouabain or l-palmitoylcarnitine shifted membrane current inward in the presence of 5.4 mM extracellular potassium. Reduction of extracellular potassium to 0 mM for 2 min also shifted membrane current inward. When extracellular potassium was returned to 5.4 mM, the intracellular sodium that had accumulated was extruded and a transient outward current was generated as a result of Na/K pump stimulation. Ouabain or l-palmitoylcarnitine reversibly suppressed this transient outward current and reduced the rate constant for the decline of this current. The ability of l-palmitoylcarnitine to imitate the actions of ouabain on membrane current and on the transient outward current indicates that this amphiphile inhibits the Na/K pump current in guinea-pig ventricular myocytes. This results is consistent with the suppression by l-palmitoylcarnitine of the activity of Na/K ATPase in cardiac sarcolemmal vesicles.

Animals↗
PubMed1992

Ruthenium red selectively prevents Ins(1,4,5)P3-but not caffeine-gated calcium release in avian atrium.

We previously reported that inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and caffeine evoked contractures in saponin-permeabilized chick atria. The magnitude of contractures evoked by maximally effective concentrations of Ins(1,4,5)P3 were half those evoked by maximally effective concentrations of caffeine. In the present report, we tested the hypothesis that these two agents may act on distinct calcium-release mechanisms by comparing the effects of ryanodine, ruthenium red, and procaine on the responses to Ins(1,4,5)P3 and caffeine. We find that procaine inhibits both responses with similar mean inhibitory concentrations in the millimolar range. Nanomolar concentrations of ryanodine selectively potentiate the contractures induced by Ins(1,4,5)P3 but have no effect on those induced by caffeine. Micromolar concentrations of ryanodine inhibit responses to both Ins(1,4,5)P3 and caffeine in a use-dependent way. Ruthenium red prevents the response to Ins(1,4,5)P3 and potentiates that to caffeine, as if ruthenium red had enhanced calcium accumulation in the caffeine-sensitive pool(s). Because we found that caffeine prevented the subsequent response to Ins(1,4,5)P3, but Ins(1,4,5)P3 had no detectable effect on the caffeine-induced contracture, we conclude that Ins(1,4,5)P3 and caffeine act on pharmacologically distinct calcium-release mechanisms that may reside in the same sarcoplasmic reticulum compartment.

Actin Cytoskeleton↗
PubMed1992

Stimulant effects of muscarinic agonists in embryonic chick ventricular muscle. Are the effects mediated by protein kinase C?

Muscarinic agonists at high concentrations produce stimulant effects in the heart. We used the embryonic chick ventricle, in which muscarinic receptor activation markedly increases phosphoinositide (PI) breakdown, to investigate the possibility that receptor-induced PI metabolism mediates the stimulant effects. In preparations paced at 0.5 to 1 Hz, carbachol (CCh; 10(-6) to 10(-3) M) shifted the action potential plateau to more positive potentials and markedly prolonged the action potential duration (APD). These effects were not associated with a change in the resting potential, did not fade with time and could be obtained in the presence of propranolol (3 x 10(-7) M) or tetrodotoxin (10(-6) M). The same effects could be obtained with acetylcholine or oxotremorine (10(-4) M) and could be suppressed with atropine (0.9 x 10(-6) M). The sensitivity of the APD to muscarinic agonists was high during early embryonic stages and declined rapidly with age. At days 3 to 5, the APD was prolonged in the presence of CCh by greater than 80% of its control value. After day 12, CCh had no prolonging effect on the APD. In nonpaced preparations, the agonist depolarized the membrane and/or induced automaticity in quiescent preparations. When automaticity was present, spontaneously or after addition of Ba++, the frequency of the automatic activity was increased by the agonist. These effects on resting potential and automaticity were also less marked in older embryos. CCh (10(-6) to 10(-4) M) evoked an atropine-sensitive positive inotropic effect in paced ventricular tissues in the presence of propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1991

Muscarinic agonist-induced actions on potassium and calcium channels in atrial myocytes: differential desensitization.

Desensitization to the effects of acetylcholine (ACh) or carbachol (CCh) on ACh-regulated potassium current (IK(ACh)) and the voltage-dependent L-type, calcium current (ICa(L)) was studied in single guinea-pig atrial cells under voltage clamp at room temperature (22-24 degrees C). At a holding potential of -40 mV, CCh (100 microM) activated IK(ACh) repeatedly and reproducibly when applied for 15-s periods with 60-s intervals between applications. Prolonged (10 min) exposure to CCh caused a time-dependent decline of IK(ACh) and a marked reduction (desensitization) of the response to subsequent application of CCh. In the absence of guanosine triphosphate (GTP) in the pipette, only partial resensitization occurred within 20 min after CCh washout. The desensitization to CCh could also be obtained when adenosine (20 microM) was used to activate this current. Therefore, this desensitization must be heterologous. In the presence of isoproterenol (ISO, 3 microM), ICa(L) increased. Acetylcholine continued to inhibit this current at a time when its activation of IK(ACh) had become desensitized. Muscarinic inhibition of ICa(L) eventually desensitized but only after IK(ACh) desensitization had occurred. Because of its heterologous nature, as well as of the ability of ACh to desensitize in the presence of intrapipette dextran, which is reported to inhibit beta-adrenergic receptor kinase (beta ARK), it seems unlikely that beta ARK-dependent phosphorylation of the muscarinic receptor (mAChR) accounted for desensitization. The differential desensitization time course is consistent with the hypothesis that different subunits of Gi, the inhibitory guanine nucleotide binding protein, not only transduce the agonist effects of ACh on IK(ACh) and ICa(L) but are also subjected to different inactivation/regulation processes.

Acetylcholine↗
PubMed1991

Inositol trisphosphate promotes Na-Ca exchange current by releasing calcium from sarcoplasmic reticulum in cardiac myocytes.

An early inward tail current evoked by membrane depolarization (from -80 to -40 mV) sufficient to activate sodium but not calcium current was studied in single voltage-clamped ventricular myocytes isolated from guinea pig hearts. Like forward-mode Na-Ca exchange, this early inward tail current required [Na+]o and [Ca2+]i and is thought to follow earlier reverse-mode Na-Ca exchange that triggers Ca2+ release from sarcoplasmic reticulum. The dependence of the early inward tail current on [Ca2+]i was supported by the ability of small (+10 mV) and large (+80 mV) voltage jumps from -40 mV to decrease and increase, respectively, the size of early inward tail currents evoked by subsequent voltage steps from -80 to -40 mV. As expected, tetrodotoxin selectively inhibited the early inward tail current but not the late inward tail current that followed voltage jumps to +40 mV test potentials. Although tetrodotoxin also blocked the fast Na+ current, replacement of extracellular Na+ by Li+ sustained the fast Na+ current. However, Li+, which does not support Na-Ca exchange, reversibly suppressed both the early and late inward tail currents. Inhibitors (ryanodine and caffeine) and promoters (intracellularly dialyzed inositol 1,4,5-trisphosphate) of sarcoplasmic reticulum Ca2+ release decreased and increased, respectively, the magnitude of the early inward tail current. The results substantiate the hypothesis that Ca2+ release from the sarcoplasmic reticulum participates in early Na-Ca exchange current and demonstrate that inositol 1,4,5-trisphosphate, by releasing Ca2+ from the sarcoplasmic reticulum, can promote Na-Ca exchange across the plasma membrane.

Animals↗
PubMed1991

Carbachol activates a novel sodium current in isolated guinea pig ventricular myocytes via M2 muscarinic receptors.

Carbachol induces a novel tetrodotoxin-resistant Na+ current in guinea pig ventricular myocytes bathed in Tyrode's solution with 20 mM Cs+. This action of carbachol, which initiates a series of reactions that culminates in a catecholamine-independent positive inotropic effect, occurs through muscarinic rather than nicotinic cholinoceptive sites. The concentrations of muscarinic antagonists required to suppress the carbachol-induced current by 50% were 2.1 nM, 270 nM, and 1700 nM for atropine, AF-DX 116, and pirenzepine, respectively. These results indicate that an M2-selective antagonist, AF-DX 116, is more potent than an M1-selective antagonist, pirenzepine, as an inhibitor. The M1-selective agonist McN-A-343 did not induce an inward current and blocked that caused by carbachol, in a rapid and reversible manner. This finding is also consistent with the conclusion that the muscarinic receptor involved in the regulation of myocardial Na+ channels by carbachol cannot be distinguished from the M2 subtype of such receptors. Treatment with pertussis toxin did not affect the ability of carbachol to induce an inward current in ventricular myocytes and reversed the current activated by carbachol in atrial cells from outward to inward. The electrophysiological and pharmacological nature of the carbachol-induced current in ventricular myocytes is very similar to that of the acetylcholine-induced current in Xenopus oocytes transfected with porcine M2, but not M1, muscarinic receptors. In both preparations, Na+ is the dominant charge carrier, intracellular Ca2+ is not involved in opening the Na+ channel, and an M2 receptor is involved.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1990

Development of cholinergic neuroeffector transmission in the avian heart. Implications for regulatory mechanisms.

A brief outline of the ontogenesis of cholinergic neuroeffector transmission in the embryonic chick heart is given. It is important to define the development of neuroeffector transmission to evaluate the possible effects on postjunctional membrane properties. The membrane response of the aneural chick heart undergoes a qualitative change to muscarinic agonist at a time well before cholinergic innervation. This suppressed response can be revealed later in life, even in adults, when provision is made to exclude Gi/Go and or K channel activity.

Acetylcholine↗
PubMed1990

Electrophysiological effects of L-palmitoylcarnitine in single ventricular myocytes.

In isolated guinea pig ventricular myocytes, L-palmitoylcarnitine (L-PC) produced concentration- and time-dependent changes of resting potential (RP) and action potential duration at 50% repolarization (APD50). At 10(-8) to 10(-6) M, L-PC increased APD50 without changing RP. At 10(-5) M, the amphiphile initially increased (0-10 min) and eventually decreased (greater than 10 min) APD50; the membrane depolarized when APD50 decreased. Additionally, transient depolarizations (TDs) were consistently induced in 10(-5) M L-PC within 10 min, and TD amplitude progressively increased with continued exposure to L-PC. The TDs induced in L-PC were augmented by membrane depolarization, elevated extracellular Ca2+ concentration ([Ca2+]o), and increased number of stimuli. Elevated [Ca2+]o or neuraminidase treatment also allowed TDs. In neuraminidase, the changes of RP, APD50, and TD amplitude were qualitatively similar to those seen with L-PC. These results are consistent with the hypothesis that 10(-5) M L-PC causes intracellular Ca2+ overload. The blockade of L-PC and neuraminidase-induced TDs by ryanodine is consistent with the intracellular Ca2+ overload hypothesis.

Animals↗
PubMed1989

Sodium-dependent membrane current induced by carbachol in single guinea-pig ventricular myocytes.

1. In the presence of either barium (0.2 mM) or caesium (20 mM), carbachol (3-300 microM) depolarized isolated guinea-pig ventricular myocytes. Carbachol induced an inward current under voltage clamp at a holding potential equal to the resting potential (-75 mV). 2. Acetylcholine and oxotremorine also evoked an inward current but were less effective than carbachol. Atropine (0.3 microM) prevented the depolarization and inward current induced by carbachol and acetylcholine but not by oxotremorine. Moreover, oxotremorine, but not carbachol, induced an inward current in the absence of extracellular sodium. 3. Carbachol increased membrane chord conductance when it induced an inward current. These effects were recorded under experimental conditions that suppressed the voltage- and time-dependent sodium current (tetrodotoxin) and calcium current (cadmium), the inwardly rectifying potassium current, iK1 (caesium, barium and tetraethylammonium) and the current generated by the sodium-potassium pump (zero external potassium). 4. Under these same experimental conditions, the steady-state I-V relationship in the presence of carbachol was subtracted from that in its absence. The apparent reversal potential (Erev) was 25 mV with extracellular Na+ ([ Na+]o) at 143 mM and intracellular Na+ ([Na+]i) at 11 mM. Replacement of [Na+]o by N-methyl-D-glucamine was associated with a shift of the apparent Erev to more negative voltages by approximately 61 mV per tenfold change of [Na+]o. 5. Isoprenaline induced an inward current in ventricular myocytes that depended upon sodium entry, required the accumulation of cyclic AMP and which was partially suppressed by acetylcholine (Egan, Noble, Noble, Powell, Twist & Yamaoka, 1988). In contrast to the current evoked by beta-adrenoceptor agonist, the current induced by muscarinic agonist was smaller and sustained. Moreover, the carbachol-induced current was not suppressed by prior addition of isoprenaline. 6. The findings are consistent with the mechanism that carbachol activates a plasma membrane ion channel that admits sodium and thereby increases intracellular sodium activity. The estimated increase of intracellular sodium activity from electrophysiological data agrees quantitatively with that obtained from measurements with sodium-sensitive microelectrodes (Korth & Kühlkamp, 1985). 7. The ability of carbachol to increase sodium influx may be the first step in a series of reactions that eventually alters sodium-calcium exchange and could account for catecholamine-independent stimulation of developed force in mammalian ventricle.

Acetylcholine↗
PubMed1988

Calcium ions and 1-palmitoyl carnitine reduce erythrocyte electrophoretic mobility: test of a surface charge hypothesis.

In ventricular muscle, 1-palmitoyl carnitine (1-PC) acted like calcium ions to shift the voltage-dependent inactivation of excitatory ion currents to less negative potentials. We proposed that 1-PC affected ion current kinetics by reducing surface negative charge. This hypothesis was tested in cell electrophoresis experiments where the electrophoretic mobility (EPM) of erythrocytes was measured in the absence and presence of test ligands. Calcium (0.18 to 3.6 mM) or 1-PC (10(-7) to 10(-6) M) reduced erythrocyte EPM in a concentration-dependent manner; the maximum reduction of EPM by either ligand was approximately 40%. In the presence of calcium, 1-PC produced a smaller decrement of EPM as expected from an occlusive interaction. Treatment of erythrocytes to remove sialic acids not only predictably reduced EPM but also diminished the ability of 1-PC and calcium to do so. These results indicate that the surface negative charge of sialic acid carboxyl groups is an important determinant both of erythrocyte EPM and of erythrocyte interaction with either 1-PC or calcium. The findings are consistent with the surface charge hypothesis for 1-PC action. We propose that 1-PC is not a neutral molecule at the cell surface but is able to neutralize surface negative charge by electrostatic interaction between the sialic acid carboxyl groups and the 1-PC quaternary ammonium moiety on the one hand and between the 1-PC carboxyl group and counterions near the membrane surface.

Calcium↗
PubMed1988

Carbachol depolarizes and accelerates pacemaker activity in the sinoatrial node of chicks treated with pertussis toxin.

Carbachol hyperpolarized the membrane of sinoatrial (SA) node cells from saline-treated chicks in a concentration-dependent fashion (10(-8)-10(-4) M). The rate of spontaneous impulse generation diminished in the presence of carbachol; complete inhibition (arrest) occurred at 10(-6) M. The hyperpolarization and negative chronotropic effect of carbachol (10(-8)-10(-6) M) were prevented by pretreatment of chicks with islet activating protein. Treatment with islet activating protein, which inactivates the guanine nucleotide binding proteins Gi and Go unmasked "stimulant" effects at high (greater than or equal to 10(-5) M) concentrations of carbachol. The stimulant effects included membrane depolarization and an acceleration of spontaneous impulse generation detected at 10(-5) and 10(-4) M carbachol, respectively. Because the depolarization and acceleration produced by carbachol occurred in the presence of propranolol, they are independent of endogenous catecholamines. As with the inhibition of the SA node, the stimulation by carbachol was mediated by muscarinic receptors and prevented by atropine. We speculate that the depolarization of SA node cells by carbachol, as in left atrium, may be mediated by products of phosphoinositide metabolism because phosphoinositide hydrolysis is activated at the same concentrations (greater than or equal to 10(-5) M). The ionic mechanism for the carbachol-induced depolarization and acceleration in SA node cells is not known. By analogy with results in left atrial cells from islet activating protein-treated animals, the mechanism would involve an increased intracellular Na+ activity and stimulation of Na-Ca exchange.

Animals↗
PubMed1987

Ontogenetic changes in adenylate cyclase, cyclic AMP phosphodiesterase and calmodulin in chick ventricular myocardium.

The activities of cyclic AMP phosphodiesterase (3',5'-cyclic nucleotide 5'-nucleotidohydrolase, EC 3.1.4.17) and adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] and calmodulin content during development of chick ventricular myocardium were determined. The specific activity of cyclic AMP phosphodiesterase was relatively low in early embryos, increased during embryogenesis by about 4-fold to reach highest values just before hatching, and then decreased by approx. 30% within 1 week after hatching. In contrast, adenylate cyclase did not change during embryonic development, but increased by approx. 50% within 1 week after hatching. Calmodulin content remained constant at 9 micrograms/g wet wt. during embryonic development and decreased to 6 micrograms/g wet wt. by 1 week after hatching. DEAE-Sephacel chromatography of chick ventricular supernatant revealed a single major form of cyclic nucleotide phosphodiesterase activity in early embryonic (9-day E) and hatched (6-day H) chicks. This enzyme form was eluted at approx. 0.27 M-sodium acetate, hydrolysed both cyclic AMP and cyclic GMP, and was sensitive to stimulation by Ca2+-calmodulin, with an apparent Km for calmodulin of approx. 1 nM. In contrast, ventricular supernatant from late-embryonic (18-day E) chicks contained two forms of phosphodiesterase separable on DEAE-Sephacel: the same form as that seen at other ages, plus a cyclic AMP-specific form which was eluted at approx. 0.65 M-sodium acetate and was insensitive to stimulation by Ca2+-calmodulin. The ontogenetic changes in cyclic AMP phosphodiesterase activity in chick ventricular myocardium are consistent with reported ontogenetic changes in the steady-state contents of cyclic AMP in this tissue and suggest that this enzyme may be responsible for the changes that occur in this nucleotide during development of chick myocardium.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Positive inotropic effects of acetylcholine and BAY K 8644 in embryonic chick ventricle.

BAY K 8644 augmented Ca2+-dependent action potentials and evoked a positive inotropic effect in embryonic chick ventricle. These effects are consistent with the properties of this Ca channel "agonist" whose actions are independent of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent phosphorylation. At low to intermediate concentrations (10(-8) to 10(-6) M), the cholinergic agonists acetylcholine, carbachol, and oxotremorine inhibit Ca2+-dependent action potentials and contractions in embryonic ventricle only in the presence of drugs that cause cAMP accumulation. The prediction that low to intermediate concentrations of these cholinergic agonists should not inhibit the effects of BAY K 8644 on Ca2+-dependent action potentials and contractions was borne out experimentally. This result is consistent with the cAMP hypothesis for muscarinic inhibition. It is noteworthy that all cholinergic agonists tested evoked a positive inotropic effect at high concentrations (greater than 10(-6) M) in the presence or absence of BAY K 8644. The positive inotropic effect was initiated by muscarinic receptors for it was blocked by atropine and was independent of endogenous catecholamines, since it occurred in the presence of propranolol. It is speculated that the positive inotropic effect of muscarinic agonists in embryonic heart muscle is related to stimulation of phosphoinositide metabolism.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1987

Pertussis toxin-insensitive phosphoinositide hydrolysis, membrane depolarization, and positive inotropic effect of carbachol in chick atria.

Muscarinic agonists can stimulate rather than inhibit cardiac muscle in some preparations. In left atria from hatched chicks, treatment with pertussis toxin reversed the membrane action of carbachol from hyperpolarization to depolarization and reversed the inotropic effect of carbachol from negative to positive. Acetylcholine also depolarized the membrane and increased the force of contraction in atria from pertussis-toxin-treated chicks although oxotremorine did not. These cholinergic responses were blocked by atropine but not by adrenoceptor antagonists, suggesting that they are mediated via muscarinic receptors and are not due to actions of endogenously released catecholamines. Muscarinic receptor stimulation leads to two distinct biochemical responses in chick atria: inhibition of adenylate cyclase and activation of phosphoinositide (PI) hydrolysis. The former is lost in atria from pertussis-toxin-treated chicks, whereas the PI response persists. The pharmacologic characteristics of the PI response resemble those of the depolarization and positive inotropic response. Both are insensitive to blockade by pertussis toxin, require high concentrations of carbachol, and are elicited by acetylcholine but not by oxotremorine. The present study suggests that muscarinic agonist-induced PI turnover may be responsible for the membrane depolarization and positive inotropic effects of carbachol and acetylcholine; that an increase in Na+ conductance underlies these responses; and that it is stimulated either by an increase of intracellular calcium mobilized by inositol triphosphate and/or by activation by protein kinase C.

Adenylate Cyclase Toxin↗
PubMed1987

Positive vs. negative inotropic effects of carbachol in avian atrial muscle: role of Ni-like protein.

Treatment with pertussis toxin not only prevents inhibitory effects (e.g., reduced adenylate cyclase activity, decreased voltage-dependent Ca2+ entry, increased K+ efflux, and negative inotropy) but also unmasks stimulant effects (e.g., membrane depolarization and positive inotropy) of carbachol in chick atria. Pertussis toxin prevents transducer proteins (Ni and No) from linking muscarinic receptors to either adenylate cyclase and Ca2+ channels or K+ channels. However, pertussis toxin treatment does not block N proteins linking the muscarinic receptor to stimulant membrane effects. Membrane depolarization by carbachol, attributed by others to increased Na+ entry, may stimulate Na-Ca exchange and positive inotropy, perhaps by activation of phospholipase D. Alternatively, carbachol could increase inositol triphosphate content and thereby release Ca2+ from the sarcoplasmic reticulum to increase the force of contraction. The ability of carbachol to increase phosphoinositide hydrolysis is resistant to pertussis toxin. The second-messenger role of phospholipid metabolites provides a foundation for testing the hypothesis that such metabolites are eventually involved in the stimulant actions of carbachol seen in pertussis toxin-treated preparations.

Adenylate Cyclase Toxin↗